Ravulizumab (1) – Ultomiris®

• Clinical trials
  • Study 301 was a randomised, open-label, controlled, two-arm parallel-group trial comparing ravulizumab with eculizumab in adult patients with PNH who had not previously been treated with a complement inhibitor.
  • Study 302 was a randomised, open-label, controlled, two-arm, parallel-group trial investigating ravulizumab compared with eculizumab in adult patients with PNH who had previously been treated with eculizumab for ≥ 6 months and were clinically stable.

a) Adult patients with paroxysmal nocturnal haemoglobinuria (PNH) with high disease activity, characterised by clinical symptoms of haemolysis

• For adult patients with PNH with high disease activity, characterised by clinical symptoms of haemolysis, the additional benefit over eculizumab is not proven.
• mortality
  • No deaths occurred in Study 301 up to week 26.
• Morbidity – Severe adverse vascular events (MAVE)
  • No statistically significant difference was observed between the treatment groups for the MAVE endpoint.
• Morbidity – Fatigue (FACIT-Fatigue)
  • No statistically significant difference was observed between the treatment groups for the fatigue endpoint.
• Morbidity – Avoidance of transfusions
  • No statistically significant difference was observed between the treatment groups for the transfusion avoidance endpoint.
• Morbidity – Breakthrough haemolysis
  • Due to the uncertainties described above regarding the operationalisation of the breakthrough haemolysis endpoint, this endpoint is not included in the present assessment of additional benefit.
• quality of life
  • In Study 301, there was no statistically significant difference between the treatment groups across the six different functional scales of the EORTC QLQ30-C30.
• Side effects
  • Up to week 26, there were no discontinuations due to adverse events nor any meningococcal infections in Study 301.
  • For the SUEs endpoint, there was no statistically significant difference between the treatment groups.
• Overall assessment / Conclusion
  • Data on mortality, morbidity, quality of life and side effects are available for the assessment of the additional benefit of ravulizumab in the treatment of adult patients with PNH with high disease activity, characterised by clinical symptoms of haemolysis.
  • No deaths occurred in the study presented; consequently, no difference was observed between the treatment groups with regard to the mortality endpoint.
  • With regard to the patient-relevant endpoints MAVE, fatigue and avoidance of transfusions within the morbidity category, there is no difference between ravulizumab and eculizumab.
  • There are neither advantages nor disadvantages with regard to health-related quality of life as measured using the EORTC-QLQ-C30.
  • The data presented show no statistically significant difference in the incidence of side effects.
  • Overall, therefore, there are neither positive nor negative effects of ravulizumab compared with eculizumab; consequently, on balance, no added benefit has been demonstrated for ravulizumab in the treatment of adult patients with PNH with high disease activity, characterised by clinical symptoms of haemolysis, additional benefit is not proven.

b) Adult patients with paroxysmal nocturnal haemoglobinuria (PNH) who have been receiving eculizumab for ≥ 6 months and are clinically stable

• For adult patients with PNH who have been receiving eculizumab for ≥ 6 months and are clinically stable, the additional benefit compared with eculizumab is not proven.
• It should be indicated that the respective operationalisations of the endpoints in Study 302 were carried out in the same way as the assessment of the respective endpoints in Study 301. The explanations regarding the individual endpoints therefore apply to Study 302 as described above.
• mortality
  • No deaths occurred in Study 302 up to week 26.
• Morbidity – Severe Adverse Vascular Events (MAVE)
  • No MAVE occurred in Study 301 up to week 26.
• Morbidity – Fatigue (FACIT-Fatigue)
  • No statistically significant difference was observed between the treatment groups in terms of fatigue, as measured using the FACIT-Fatigue scale.
• Morbidity – Avoidance of transfusions
  • No statistically significant difference was observed between the treatment groups for the endpoint of transfusion avoidance.
• Morbidity – Breakthrough haemolysis
  • Due to the uncertainties described above regarding the operationalisation of the breakthrough haemolysis endpoint, this endpoint is not included in the present assessment of additional benefit.
• quality of life
  • For 5 out of 6 items on the EORTC QLQ-C30 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, social functioning), there is no statistically significant difference between the treatment groups.
  • For the item ‘global health status’, there is a statistically significant advantage in favour of ravulizumab over eculizumab. (1.8 vs. –2.7; MD 4.52 [95% CI 0.17; 8.87]; p = 0.042). However, the clinical relevance of this effect cannot be conclusively assessed, as the 95% CI of the standardised mean difference does not lie entirely outside the irrelevance range of –0.2 to 0.2 (Hedges’ g: 0.29 [0.01; 0.57]).
• Side effects
  • Up to week 26, there were no discontinuations due to adverse events nor any meningococcal infections in study 302.
  • For the endpoint SUEs, there was no statistically significant difference between the treatment groups.
• Overall assessment / Conclusion
  • Data on mortality, morbidity, quality of life and side effects are available for the assessment of the additional benefit of ravulizumab in the treatment of adult patients with PNH who have been receiving eculizumab for ≥ 6 months and are clinically stable.
  • No deaths occurred in the studies presented; consequently, no difference was observed between the treatment groups with regard to the mortality endpoint.
  • With regard to the endpoints MAVE, fatigue and avoidance of transfusions in the morbidity category, there is no difference between ravulizumab and eculizumab.
  • There are neither advantages nor disadvantages with regard to health-related quality of life as measured using the EORTC-QLQ-C30.
  • The data presented show no statistically significant difference in the incidence of side effects.
  • Overall, therefore, there are neither positive nor negative effects of ravulizumab compared with eculizumab; consequently, additional benefit is not proven for ravulizumab in the treatment of adult patients with PNH who have been receiving eculizumab for ≥ 6 months and are clinically stable.

Courtesy translation only, please refer to the German original.